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Short Telomeres Compromise β-Cell Signaling and Survival
The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres,...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053388/ https://www.ncbi.nlm.nih.gov/pubmed/21423765 http://dx.doi.org/10.1371/journal.pone.0017858 |
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author | Guo, Nini Parry, Erin M. Li, Luo-Sheng Kembou, Frant Lauder, Naudia Hussain, Mehboob A. Berggren, Per-Olof Armanios, Mary |
author_facet | Guo, Nini Parry, Erin M. Li, Luo-Sheng Kembou, Frant Lauder, Naudia Hussain, Mehboob A. Berggren, Per-Olof Armanios, Mary |
author_sort | Guo, Nini |
collection | PubMed |
description | The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. In ex vivo studies, short telomeres induced cell-autonomous defects in β-cells including reduced mitochondrial membrane hyperpolarization and Ca(2+) influx which limited insulin release. To examine the mechanism, we looked for evidence of apoptosis but found no baseline increase in β-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of β-cells and accumulation of p16(INK4a). Specifically, we identified gene expression changes in pathways which are essential for Ca(2+)-mediated exocytosis. We also show that telomere length is additive to the damaging effect of endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This additive effect manifests as more severe hyperglycemia in Akita mice with short telomeres which had a profound loss of β-cell mass and increased β-cell apoptosis. Our data indicate that short telomeres can affect β-cell metabolism even in the presence of intact β-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of β-cell function and diabetes pathogenesis. |
format | Text |
id | pubmed-3053388 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30533882011-03-18 Short Telomeres Compromise β-Cell Signaling and Survival Guo, Nini Parry, Erin M. Li, Luo-Sheng Kembou, Frant Lauder, Naudia Hussain, Mehboob A. Berggren, Per-Olof Armanios, Mary PLoS One Research Article The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. In ex vivo studies, short telomeres induced cell-autonomous defects in β-cells including reduced mitochondrial membrane hyperpolarization and Ca(2+) influx which limited insulin release. To examine the mechanism, we looked for evidence of apoptosis but found no baseline increase in β-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of β-cells and accumulation of p16(INK4a). Specifically, we identified gene expression changes in pathways which are essential for Ca(2+)-mediated exocytosis. We also show that telomere length is additive to the damaging effect of endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This additive effect manifests as more severe hyperglycemia in Akita mice with short telomeres which had a profound loss of β-cell mass and increased β-cell apoptosis. Our data indicate that short telomeres can affect β-cell metabolism even in the presence of intact β-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of β-cell function and diabetes pathogenesis. Public Library of Science 2011-03-10 /pmc/articles/PMC3053388/ /pubmed/21423765 http://dx.doi.org/10.1371/journal.pone.0017858 Text en Guo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Guo, Nini Parry, Erin M. Li, Luo-Sheng Kembou, Frant Lauder, Naudia Hussain, Mehboob A. Berggren, Per-Olof Armanios, Mary Short Telomeres Compromise β-Cell Signaling and Survival |
title | Short Telomeres Compromise β-Cell Signaling and Survival |
title_full | Short Telomeres Compromise β-Cell Signaling and Survival |
title_fullStr | Short Telomeres Compromise β-Cell Signaling and Survival |
title_full_unstemmed | Short Telomeres Compromise β-Cell Signaling and Survival |
title_short | Short Telomeres Compromise β-Cell Signaling and Survival |
title_sort | short telomeres compromise β-cell signaling and survival |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053388/ https://www.ncbi.nlm.nih.gov/pubmed/21423765 http://dx.doi.org/10.1371/journal.pone.0017858 |
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